RESUMO
The BB (BioBreeding) rat is one of the best models of spontaneous autoimmune diabetes and is used to study non-MHC loci contributing to Type 1 diabetes. Type 1 diabetes in the diabetes-prone BB (BBDP) rat is polygenic, dependent upon mutations at several loci. Iddm1, on chromosome 4, is responsible for a lymphopenia (lyp) phenotype and is essential to diabetes. In this study, we report the positional cloning of the Iddm1/lyp locus. We show that lymphopenia is due to a frameshift deletion in a novel member (Ian5) of the Immune-Associated Nucleotide (IAN)-related gene family, resulting in truncation of a significant portion of the protein. This mutation was absent in 37 other inbred rat strains that are nonlymphopenic and nondiabetic. The IAN gene family, lying within a tight cluster on rat chromosome 4, mouse chromosome 6, and human chromosome 7, is poorly characterized. Some members of the family have been shown to be expressed in mature T cells and switched on during thymic T-cell development, suggesting that Ian5 may be a key factor in T-cell development. The lymphopenia mutation may thus be useful not only to elucidate Type 1 diabetes, but also in the function of the Ian gene family as a whole.
Assuntos
Diabetes Mellitus Tipo 1/genética , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/genética , Linfopenia/genética , Deleção de Sequência/genética , Sequência de Aminoácidos , Animais , Animais Congênicos/genética , Proteínas Reguladoras de Apoptose , Diabetes Mellitus Tipo 1/complicações , Proteínas de Ligação ao GTP/biossíntese , Células-Tronco Hematopoéticas/química , Células-Tronco Hematopoéticas/metabolismo , Humanos , Linfopenia/etiologia , Camundongos , Dados de Sequência Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Tirosina Fosfatase não Receptora Tipo 22 , Proteínas Tirosina Fosfatases/genética , Ratos , Ratos Endogâmicos BB , Ratos Endogâmicos F344 , Ratos Endogâmicos LEC , Ratos Endogâmicos OLETFRESUMO
Dietary factors have been reported to affect the development of spontaneous diabetes in various colonies of inbred and outbred diabetes-prone (DP) BioBreeding (BB) rats. Several studies have attributed a protective effect to a diet omitting crude protein mixtures in favor of purified casein, hydrolyzed casein, or free amino acids. We have used inbred BB rats, all of which become diabetic in specific pathogen-free (SPF) conditions when fed ordinary rat chow, to test the capacity of 2 different protein-free diets to modulate BB rat diabetes in 2 distinct pathogen-free environments. BB rats known to all develop diabetes by 100 days of age were fed from birth with 1 of 3 diets. By 120 days of age, 100% of the animals on a standard diabetogenic chow diet, 83% of animals on an amino acid-based protein-free diet, and 100% of animals on a hydrolyzed casein-based diet had developed diabetes (P >.05). A slight delay in the age of onset was observed among rats fed the amino acid-based diet, but this delay coincided with a reduction in weight gain among these animals compared with the rats on a standard diet. Histology showed insulitis in all rats at either diabetes onset or 120 days of age. We conclude that our unique strain of specific pathogen-free BB rats are not protected from diabetes when fed an amino acid-based diet and suggest that their insensitivity to dietary manipulation may be due to an as yet unknown factor present in the diabetes-resistant (DR), but not the DP BB rat genetic background.
